RASSF4, a protein-coding gene, is regarded as a tumor suppressor often regulated by DNA methylation. It binds directly to activated K-Ras in a GTP-dependent manner, acting as a Ras effector. RASSF4 participates in multiple biological processes, such as regulating intracellular store-operated Ca2+ entry, which impacts cell survival, and is involved in the Hippo signaling pathway [1,4].

In metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC), liver-specific RASSF4 knockout mouse models demonstrated that loss of hepatic RASSF4 exacerbated hepatic steatosis and fibrosis, while its overexpression prevented steatosis. RASSF4 in hepatocytes also suppressed the activation of hepatic stellate cells. Mechanistically, RASSF4 in the liver interacts with MST1 to inhibit YAP nuclear translocation through the Hippo pathway, establishing it as a therapeutic target for MASLD and HCC [2]. In colorectal cancer, RASSF4 was downregulated, and its overexpression in LoVo cells inhibited cell growth, colony formation, and cell cycle progression, and increased sensitivity to 5-FU treatment through the YAP/Bcl-2 pathway [3].

In conclusion, RASSF4 plays crucial roles in multiple biological processes and disease conditions. The use of gene knockout mouse models, especially in liver-related diseases like MASLD and HCC, has revealed its importance in regulating steatosis, fibrosis, and carcinogenesis, providing potential therapeutic targets for these diseases.

References:

1. Liu, Aimei, Zhou, Kaixiang, Martínez, María Aránzazu, Anadón, Arturo, Ares, Irma. 2021. A "Janus" face of the RASSF4 signal in cell fate. In Journal of cellular physiology, 237, 466-479. doi:10.1002/jcp.30592. https://pubmed.ncbi.nlm.nih.gov/34553373/

2. Xu, Chaofei, Fang, Ting, Qu, Jingru, Sun, Bei, Chen, Liming. 2024. RASSF4 Attenuates Metabolic Dysfunction-Associated Steatotic Liver Disease Progression via Hippo Signaling and Suppresses Hepatocarcinogenesis. In Cellular and molecular gastroenterology and hepatology, 18, 101348. doi:10.1016/j.jcmgh.2024.04.005. https://pubmed.ncbi.nlm.nih.gov/38697356/

3. Han, Yong, Zhang, Xiaotang, Guan, Minmin, Hu, Bin, Cai, Jianjun. 2022. RASSF4 inhibits cell proliferation and increases drug sensitivity in colorectal cancer through YAP/Bcl-2 pathway. In Journal of cellular and molecular medicine, 26, 3538-3547. doi:10.1111/jcmm.17395. https://pubmed.ncbi.nlm.nih.gov/35611809/

4. Chen, Yu-Ju, Chang, Chi-Lun, Lee, Wan-Ru, Liou, Jen. 2017. RASSF4 controls SOCE and ER-PM junctions through regulation of PI(4,5)P2. In The Journal of cell biology, 216, 2011-2025. doi:10.1083/jcb.201606047. https://pubmed.ncbi.nlm.nih.gov/28600435/